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Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency.
Molecular Therapy - Oncolytics ( IF 5.7 ) Pub Date : 2020-01-11 , DOI: 10.1016/j.omto.2019.12.013
Yu-Shui Ma 1, 2 , Xiao-Feng Wang 3 , Yun-Jie Zhang 3 , Pei Luo 1 , Hui-Deng Long 1 , Liu Li 1 , Hui-Qiong Yang 1 , Ru-Ting Xie 1 , Cheng-You Jia 2 , Gai-Xia Lu 2 , Zheng-Yan Chang 1 , Jia-Jia Zhang 2 , Shao-Bo Xue 1 , Zhong-Wei Lv 2 , Fei Yu 2 , Qing Xia 3 , Da Fu 1
Affiliation  

Functional elimination of p53 is a common feature of a large percentage of human malignancies. Here, we report the development of a pharmacological strategy aimed at restoring p53 function and its use for targeted therapy in p53-deficient mice. Specific inhibition of deubiquitinases ubiquitin-specific peptidase 14 (USP14) resulted in durable tumor regressions of autochthonous lymphomas and sarcomas in p53-deficient mice without affecting normal tissues, and therapeutic response was correlated with an increase in the ubiquitination of constitutive photomorphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative regulatory effector for p53. Inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and a p53-dependent and -independent regulation mechanism by USP14. This series highlights the utility of proteasome deubiquitinating activity inhibition as a novel treatment paradigm for p53-deficient cancers. In addition, it provides preliminary evidence that inhibition of USP14 resulted in durable tumor regression through COPS5 deubiquitilation and p53-dependent and -independent regulation mechanism by USP14. These findings suggest that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target for patients with p53 deficiency.



中文翻译:

抑制USP14去泛素化活性作为p53缺乏性肿瘤的潜在疗法。

p53的功能消除是大部分人类恶性肿瘤的共同特征。在这里,我们报告了旨在恢复p53功能的药理策略的发展及其在p53缺陷小鼠中的靶向治疗的用途。去泛素化酶泛素特异性肽酶14(USP14)的特异性抑制导致p53缺陷小鼠中的本地性淋巴瘤和肉瘤持续消退而不会影响正常组织,并且治疗反应与组成型光形态发生9(COP9)的泛素化增加相关信号小体亚基5(COPS5),p53的关键负调控因子。USP14的抑制通过COPS5去泛素化和USP14的p53依赖性和非依赖性调节机制导致了持久的肿瘤消退。该系列强调了蛋白酶体去泛素化活性抑制作为p53缺陷型癌症的新型治疗范例的实用性。另外,它提供了初步的证据,即USP14的抑制通过COPS5去泛素化以及USP14的p53依赖性和非依赖性调节机制导致了持久的肿瘤消退。这些发现表明,19S调节颗粒的去泛素化活性是针对p53缺乏症患者的新抗癌药物靶标。

更新日期:2020-01-11
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